Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CMS) and is responsible for long-term morbidity in 250,000-350,000 people in the United States. Although the precise etiology of MS is unknown, it is thought to be a T-cell-mediated process due to characteristic histologic features and the presence of neuroantigen-specific immune responses in the blood and cerebrospinal fluid. Thus, several immunomodulatory therapies are being investigated to combat this disease. The vast majority of studies in EAE and MS have focused on evaluating and targeting CD4+ T cell responses. Although both diseases are thought to be mediated and regulated by CD4+ T cells, several reports from others and us present strong evidence for a role of CD8+ T cells in the pathogenesis. However, the functional relevance of autoreactive CNS-targeted CD8+ T cells remains a poorly studied aspect of MS immunopathology. Using novel immunophenotypic approaches, we have recently shown that CNS-specific autoreactive CD8+ T cell responses are far more prevalent in MS patients than appreciated thus far. Moreover, they exhibit a functional phenotype that suggests a mixed functional profile and appears distinct from autoreactive CD8+ responses in healthy subjects. We thus hypothesize that CNS-specific autoreactive CD8+ T cells play an important role in the pathogenesis and intrinsic immune modulation of MS. Through studies proposed in this application, we will evaluate the role of CNS-specific CD8+ T cells by delineating their phenotypic and functional features, their fine specificity and their activation requirements. We believe that understanding the biology of this critical aspect of the underlying immune response will provide important insights that can be utilized for therapeutic benefit in MS and other autoimmune diseases.